Howard B. A. Baum

Effects of rhIGF-I administration on bone turnover during short-term fasting.

Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages 19-33 (mean, 24 +/- 4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline). Serum levels of PICP and osteocalcin decreased from 143 +/- 52 to 60 +/- 28 ng/ml (P = 0.001) and from 7.6 +/- 5.4 to 4.2 +/- 3.1 ng/ml (P = 0.001) respectively with 4 d of fasting. Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96 +/- 63 to 47 +/- 38 nmol/mmol creatinine (P < 0.05) and from 28 +/- 17 to 14 +/- 11 nmol/mmol creatinine (P < 0.05) respectively. Mean IGF-I levels decreased from 310 +/- 81 to 186 +/- 78 ng/ml (P = 0.001). In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9 +/- 17.3 vs. 5.9 +/- 6.4 ng/ml for osteocalcin [P < 0.05] and 188 +/- 45 vs. 110 +/- 37 ng/ml for PICP [P < 0.05]). In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women. RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption. These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.

Continuing Improvement in Type 2 Diabetes Care Through Performance-Based Evaluations

Aims: The timely evidence-based care of type 2 diabetes mellitus (T2DM) is imperative for achieving and maintaining glycemic control, reducing complications, and changing the paradigm of this epidemic. Based largely on results from earlier performance improvement (PI) activities, we conducted a continuing medical education (CME)–certified PI activity to foster improved adherence to guideline recommendations and current evidence for the care of patients with T2DM. Methods: Participants engaged in a 3-stage process of self-assessment, goal setting, and reassessment. Results: A total of 64 clinicians completed the entire PI process, abstracting data from 1600 patient charts before and after a period of self-improvement. After the intervention, clinicians were more likely to assess patients for disease-related complications and provide counseling on proper nutrition, exercise, and smoking cessation. Patients with A1C, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) values above goal (defined as A1C ≥7, BP ≥130/80 mm Hg, and LDL-C >100 g/dL) were more likely to receive treatment modifications compared with baseline clinician performance. Significant changes observed in patient outcomes included improved mean A1C values (baseline 7.5% vs postintervention 7.3%; P = .027), decreased likelihood of BP at or above 130/80 mm Hg (baseline 37% vs postintervention 30%; P < .001), and decreased likelihood of LDL-C above 100 g/dL (baseline 33% vs postintervention, 27%; P < .001). Conclusions: Significant changes in clinician performance of key quality measures were reported in patients with T2DM after a PI CME activity improved adherence to evidence-based recommendations of care.

Ectopic ACTH Production Leading to Diagnosis of Underlying Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) has been described as a source of ectopic ACTH secretion in patients with Cushing’s syndrome. This is an infrequent association, occurring in less than 1% of MTC cases. Among these, it is even more unusual for an initial diagnosis of hypercortisolism to lead to the discovery of underlying MTC. Here we present a case of a patient with weakness, diarrhea, and hypokalemia who was found first to have Cushing’s syndrome and later diagnosed with metastatic MTC. The patient was treated initially with oral agents to control his hypercortisolism, then with an etomidate infusion after experiencing intestinal perforation. He also received vandetanib therapy targeting his underlying malignancy, as this has been shown to reverse clinical signs of Cushing’s syndrome in patients with MTC and subsequent ectopic ACTH secretion. Bilateral adrenalectomy was ultimately required. Medullary thyroid carcinoma should be considered in patients presenting with Cushing’s syndrome due to ectopic ACTH secretion, and a multimodality treatment approach is often required.

Growth Hormone and Osteoporosis

Since the first demonstration of the activity of human and monkey pituitary growth hormone (GH) extracts in humans (1,2), research regarding the effect of GH on bone have focused primarily on the hormone’s promotion of linear growth. In the last decade, however, the importance of the role of GH in bone metabolism has become increasingly apparent. Recent research has demonstrated that GH administration stimulates osteoblast proliferation and promotes bone formation in vitro and in vivo, and that GH deficient states are associated with osteoporosis. In addition, normal aging has been shown to be associated with both declining GH secretion and declining bone density, suggesting a possible link between GH and senile osteoporosis. A number of technical advances have aided this work. In vitro studies have been advanced by new cell-culture techniques and recombinant DNA technology. Studies of bone metabolism in humans have assessed bone turnover with a widening array of serum and urine markers. These include osteoblast markers, byproducts of bone formation, and urine markers of bone resorption. Furthermore, refinements in the measurement of bone mineral content and bone density have permitted long term studies of the effect of GH administration on bone mass. This chapter will address the relationship between GH and osteoporosis by reviewing in vitro studies of GH and bone cells, studies of patients with GH deficiency, and studies of GH administration using different model systems.